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PubMed1988

Neuronal cell differentiation of human neuroblastoma cells by retinoic acid plus herbimycin A.

We investigated the effect of retinoic acid (RA) and herbimycin A (herb-A) on cell growth, cell differentiation, and colony formation of human neuroblastoma cell lines. The neuroblastoma line SK-N-SH expressed both neuroblast and nonneuronal phenotypes, whereas its subclone SH-SY5Y and the Kelly cell line were predominantly neuroblastic. Both herb-A and RA, given alone, moderately reduced cell growth and colony formation of the neuroblastic cell lines. Growth curve analyses with SK-N-SH suggested that herb-A greatly reduced the number of initially growing cells, whereas RA slightly enhanced initial cell growth. Morphological changes were determined with the use of rhodaminephalloidin staining of actin. Retinoic acid caused an increase in the fraction of neuroblast cell in SK-N-SH, and conversely of nonneuronal cells in SH-SY5Y and Kelly cell lines. Both drugs also caused partial differentiation towards a neuronal phenotype, and herb-A induced selective lysis of nonneuronal cells of SK-N-SH. Because of their discrepant effects, RA (10 microM) and herb-A (236 nM) were tested in combination at a concentration that had only moderate effects when given alone. The combination further reduced cell growth and colony formation and dramatically enhanced differentiation towards a neuronal morphology. The Kelly cell line with amplified N-myc genome, which correlates with clinical progression of neuroblastoma, was also sensitive to RA plus herb-A. These results recommend the combination of RA and herb-A for differentiation therapy of neuroblastoma.

Anti-Bacterial Agents↗
PubMed1989

[Regulatory mechanisms of mast cell differentiation].

Mast cells are a progeny of the multipotential hematopoietic stem cell. Most of progenies of the stem cell complete their differentiation within the bone marrow, but precursors of mast cells leave the bone marrow, migrate in blood, and invade into tissues. After the invasion, precursors proliferate and differentiate into mast cells. An appreciable proportion of mast cells retain proliferative potential after differentiation, and even after degranulation, some mast cells can proliferate and recover the original morphology. Proliferation of mast cells are regulated by both T cell-derived factors (i.e., IL-3 and IL-4) and fibroblast-derived factor(s). Mice of either W/Wv or Sl/Sld genotype lack mast cells, but mast cells do develop when bone marrow cells of W/Wv or Sl/Sld mice were cultured in the presence of T cell-derived factors. Mast cells derived from W/Wv mice cannot respond fibroblast-derived factor(s) and fibroblasts derived from Sl/Sld mice cannot support mast cells of normal mouse origin. Phenotypes of mast cells are determined by the environment in which the mast cells differentiated. However, when mast cells are transplanted into a new environment which is different from the original one, the mast cells acquire the phenotype which are dependent on the second environment.

Animals↗
PubMed2006

Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells.

During embryogenesis, epicardial cells undergo epithelial-mesenchymal transformation (EMT), invade the myocardium, and differentiate into components of the coronary vasculature, including smooth muscle cells. We tested the hypothesis that transforming growth factor-beta (TGFbeta) stimulates EMT and smooth muscle differentiation of epicardial cells. In epicardial explants, TGFbeta1 and TGFbeta2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon. Inhibition of activin receptor-like kinase (ALK) 5 blocks these effects, whereas constitutively active (ca) ALK5 increases cell invasion by 42%. Overexpression of Smad 3 did not mimic the effects of caALK5. Inhibition of p160 rho kinase or p38 MAP kinase prevented the loss of epithelial morphology in response to TGFbeta, whereas only inhibition of p160 rho kinase blocked TGFbeta-stimulated caldesmon expression. These data demonstrate that TGFbeta stimulates loss of epithelial character and smooth muscle differentiation in epicardial cells by means of a mechanism that requires ALK5 and p160 rho kinase.

Activin Receptors, Type I↗
PubMed1994

Distinct pathways of B cell differentiation. I. Residual T cells in athymic mice support the development of splenic germinal centers and B cell memory without an induction of antibody.

B cell memory to T cell-dependent Ags develops in the germinal centers (GC). Here we report that thymus-deficient, nu/nu mice immunized with phosphorylcholine coupled to keyhole limpet hemocyanin (EPC-KLH) develop GC in the spleen in the absence of Ab-forming cell (AFC) response. However, the formation of GC on EPC-KLH immunization requires T cells, because 1) CB.1.7-scid mice reconstituted with B lymphocytes failed to develop GC without a supplement of CD4+ cells and 2) in vivo administration of an anti-CD4 mAb abolished the GC response in euthymic mice. Thus, it appears that the formation of GC in nu/nu mice was due to a low number of T cells that were detectable in situ within the splenic lymphoid follicles. The numbers of GC in individual Ag-stimulated nu/nu mice appeared to correlate with the density of T cells in the splenic sections. The B cells in these GC expressed T15, the dominant Id of anti-PC Ab, and became primed for an anamnestic response. Secondary challenge with EPC-KLH resulted in an increased number of GC without detectable AFC. However, when the Ag-primed nu/nu mice received CD4+ lymphocytes 1 day before the challenge, they demonstrated a vigorous AFC response that was predominantly IgM and significantly higher than the secondary response of nu/nu mice that had been reconstituted with CD4+ cells during both primary and secondary immunizations. Therefore, it appears that immunization of nu/nu mice may lead to an early step of B cell activation and memory development even though the T lymphocytes in these mice are incompetent to provide help for Ab formation. The memory and Ab pathways of B cell differentiation may involve different mechanisms of T cell help.

Animals↗
PubMed1986

T cell differentiation within thymic nurse cells.

Thymic nurse cells (TNC), defined as in vitro isolation products of thymic tissue, are epithelial cells harboring in their cytoplasm up to 200 intact, actively dividing thymocytes which are completely surrounded by vacuolar membranes. The TNC plasma membrane expresses major histocompatibility complex class I (H-2 K/D) and class II (I-A) antigens. The expression of MHC class I and class II antigens on the TNC vacuolar membranes was investigated with an improved in situ labeling technique. The major histocompatibility complex phenotype of the vacuolar membranes is H-2 K/D+, I-A2+ and thus identical to the TNC plasma membrane phenotype. By using the labeling technique, the TNC thymocyte population was examined for expression of the T cell differentiation antigens Thy-1, peanut agglutinin, Lyt-1, and Lyt-2, and the antigen expression was related to resistance of this population to cortisone. The majority of TNC thymocytes in individual TNC were cortisone-sensitive and expressed the immature phenotype of cortical thymocytes (Thy-1hi, PNAhi, Lyt-1lo, Lyt-2). A minority of the TNC thymocytes were cortisone-resistant and expressed a mature phenotype (Thy-1lo, peanut agglutininlo, Lyt-1hi). The existence of this minor mature population was confirmed in vivo: cortisone-resistant thymocytes were associated with cortical epithelial cells scattered throughout the thymic cortex of mice treated with dexamethasone. The major histocompatibility complex positive microenvironment of TNC and the heterogeneity in phenotype and resistance to cortisone of the TNC thymocytes, which is related to the state of maturation, indicate that TNC play an important role in the selection and differentiation of T cells.

Animals↗
PubMed2005

The cytoplasmic expression of E-cadherin and beta-catenin in bovine trophoblasts during binucleate cell differentiation.

Binucleate cells are endocrine cells generated by the acytokinesis and endoreduplication of the trophectoderm in the ruminant placenta. These cells are migratory and secrete hormones into the maternal circulation after fusing with uterine epithelial cells. In this study, we performed immunohistochemistry for E-cadherin and beta-catenin in bovine placenta and a bovine trophoblast cell line (BT-1). We found that E-cadherin and beta-catenin were distributed not only at the cell to cell boundary but throughout the cytoplasm in binucleate cells, although they were concentrated at the cell to cell boundary in epithelial cells in bovine placenta. Moreover, beta-catenin was detected in the nuclei of binucleate cells. Binucleate cells after fusion with uterine epithelial cells (feto-maternal hybrid cells) in the maternal side showed no intracellular expression of E-cadherin and beta-catenin. The transformation into binucleate cells in the BT-1 cell line was also accompanied by the cytoplasmic accumulation of E-cadherin and beta-catenin. We further demonstrated that levels of cytoplasmic beta-catenin were well correlated with the DNA content of binucleate cells in BT-1. The dynamic changes in the distribution of E-cadherin and beta-catenin suggest an important role in binucleate cells, including the rearrangement of cadherin-mediated cell adhesions during cell migration and the onset of endoreduplication probably via the nuclear transfer of beta-catenin.

Actins↗
PubMed2000

Expression of the actin-bundling protein fascin in cultured human dendritic cells correlates with dendritic morphology and cell differentiation.

Dendritic cells are key players of the immune system as they efficiently induce primary immune responses by activating naive T cells. We generated human dendritic cells from CD14+ blood precursors and investigated expression of the actin-bundling protein fascin during maturation by western blotting, immunofluorescence, and cytofluorometry. Cells obtained by culture of CD14+ blood precursors in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4, which were only weakly positive for the maturation marker CD83, expressed low amounts of fascin. Addition of a cytokine cocktail including tumor necrosis factor alpha, interleukin-1beta, interleukin-6, and prostaglandin E2 induced maturation of the cells and enhanced fascin expression in parallel with CD83 expression. Isolated mature CD83+ cells displayed especially high fascin levels on western blots, as did gated CD83+ dendritic cells in cytofluorometry. Dendritic cells generated from CD34+ blood precursors expressed high levels of fascin as well. Confocal microscopy revealed that location of fascin within the cell was restricted to the area of the submembranous actin cytoskeleton and to the dendritic processes. Suppression experiments using antisense constructs of fascin hint at a retarded morphologic maturation of dendritic cells, supporting the view that fascin expression is pivotal for dendrite formation. Our data suggest that fascin could serve as a marker molecule to monitor the maturation state of in vitro generated dendritic cells for use in clinical trials.

Actins↗
PubMedDate not supplied

Fine needle aspiration cytodiagnosis of Hodgkin's disease and its subtypes. II. Subtyping by differential cell counts.

Differential cell counts were performed on fine needle aspiration (FNA) smears from 96 cytologically diagnosed and subsequently biopsy-proven cases of Hodgkin's disease (HD). Reed-Sternberg cells and Hodgkin cells showed a definitely increasing trend in three major HD subtypes (as diagnosed on the smears): lymphocytic predominance (LP), mixed cellularity (MC) and lymphocytic depletion (LD). Lymphocytes, on the other hand, showed a decreasing trend between these subtypes. The differences in the percentages of Hodgkin cells, Reed-Sternberg cells and lymphocytes were highly significant (P less than .001). No trends (increasing or decreasing) were observed in the smear content of other reactive components (non-neoplastic histiocytes, eosinophils, plasma cells and neutrophils). In 88.0% to 95.0% of the cytologically diagnosed cases of LP, MC and LD subtypes, the percentages of Hodgkin cells plus Reed-Sternberg cells fell within a distinct range: less than 1.5% for LP, greater than or equal to 1.5% to less than 7.5% for MC and greater than or equal to 7.5% for LD. Analysis of the data based on histopathologic subtyping of the cases showed similar significant trends in the proportions of Hodgkin cells, Reed-Sternberg cells and lymphocytes, with 70.0% to 80.0% of the LP, MC and LD subtype cases within these ranges. These results demonstrate the validity of the subjective subtyping of HD on FNA smears in most cases.

Adult↗
PubMed2005

Morphine withdrawal contributes to Th cell differentiation by biasing cells toward the Th2 lineage.

The consequences that drug withdrawal has on immune functioning has only recently been appreciated; however, given the wide variety of use and abuse of opiate analgesics, understanding the decrements to immune function that withdrawal from these drugs causes is of crucial importance. In previous work, we have demonstrated that morphine treatment contributes to immunosuppression by polarizing Th cells toward the Th2 lineage. In the current study, it was hypothesized that morphine withdrawal would result in Th2 differentiation and subsequent immune dysfunction. To address this hypothesis, mice were chronically treated with morphine for 72 h followed by a 24-h withdrawal period. It was determined that 24-h morphine withdrawal resulted in a decrease in IFN-gamma, the Th1 signature cytokine, whereas the Th2 cytokine, IL-4, was increased. In addition, Western blot and EMSA experiments revealed that morphine withdrawal-induced Th2 differentiation was mediated through the classical Th2 transcription factors Stat-6 and GATA-3. In addition, the consequence of morphine withdrawal in the presence of an immune stimulation was also examined by treating mice in vivo with LPS before morphine withdrawal. Following withdrawal, it was found that the Th1-polarizing cytokine IL-12 was significantly decreased, providing further support for the observation that withdrawal results in Th2 differentiation by possibly impacting the generation of an appropriate innate immune response which directs subsequent adaptive Th1/Th2 responses.

Active Transport, Cell Nucleus↗
PubMed1980

The critical role of the nucleolus in cell differentiation and stem cell development - an extension of the concept with a look at the mast cell and its possible role in zinc metabolism.

From the assumptions governing the behaviour of primitive cells, a set of corollaries is established and the corollaries are used in coming to an understanding of the growth and differentiation of the pancreas. A case is made out to show that there is a constant replacement of old acini by new throughout the life of the pancreas, and that new acini are derived from primitive cells (fixed reticulum cells) present in the stroma which envelopes the fine ducts. The part played by the mast cells in the process is discussed, and view put forward that circulating thymocytes are mast cell precursors, and that the function of the mast cell is to provide the primitive cells of the pancreas (and the primitive cells of certain other tissues) with Zn in an assimilatable form. The hypothesis is made that Zn can only be assimilated by primitive cells, and, that for organs other than the thymus, it is assimilated in the form of the histamine-Zn complex liberated by the mast cells. The fate of the mast cell is analysed, and the suggestion made that, following degranulation, the mast cell nucleus is transformed into a cell of the eosinophil series. The role of the basophil is also analysed, and the conclusion reached that basophils are mast cells whose development has been modified by plasma.

Basophils↗
PubMed1994

Polyclonal in vitro T cell proliferation and T cell-dependent B cell differentiation supported by activated autologous B cells.

Although anti-CD3-induced T cell proliferation and T cell-dependent B cell differentiation are not supported well by resting (nonactivated) B cells as AC, human peripheral blood B cells activated in vitro with SAC, rIL2, or anti-IgM effectively subserve AC function in a manner qualitatively similar to that of blood monocytes and support polyclonal anti-CD3-driven T cell-dependent B cell differentiation. Physical contact among T cells, responder B cells, and (irradiated) activated B cells is required, and the ability of activated B cells to support anti-CD3-driven generation of IgSC parallels surface B7 expression by the activated B cells. The fusion protein CTLA4Ig, which binds to B7 and B7-like molecules with high avidity and disrupts the interaction of T cell surface CD28 with B7, inhibits B cell differentiation in a dose-dependent fashion, whereas a control fusion protein has no such effect. Thus, activated B cells support polyclonal T cell-dependent B cell differentiation via a CD28 (CTLA4)/B7 (B7-like)-dependent mechanism.

Abatacept↗
PubMed1987

Tumor cell rejection through terminal cell differentiation.

Leukemic cells cultured in the presence of various conditioned media differentiate into macrophages. This finding suggested that the maintenance of undifferentiated state and self-renewal in vivo may be related to the inability of the host to generate an appropriate level of differentiation factor (DF). Evidence for this hypothesis was derived from experiments in vitro and in vivo with myeloid leukemia of rat. The following results were obtained: (i) in vitro, the percentage of cell differentiation at a fixed concentration of DF was inversely related to the concentration of cells; (ii) leukemic cell inoculates that were lethal to 7-day-old rats were rejected by 21-day-old rats; (iii) leukemic cells in diffusion chambers underwent differentiation in 21-day-old rats but not in 7-day-old rats; (iv) organs from 21-day-old rats contained more DF activity than those of 7-day-old rats; (v) treatment of rats with DF in diffusion chambers resulted in leukemic cell differentiation inside the chamber; and (vi) the development of leukemia in 7-day-old rats was aborted by treatment with DF. These results show that the differentiation of rat leukemia cells requires the appropriate level of DF. The proliferation of transplanted leukemia cells in 7-day-old rats goes unchecked because of inadequate generation of DF. Conversely, in the 21-day-old rats, rejection is accomplished by differentiation of the transplanted cells.

Animals↗
PubMed1980

Survival of mice inoculated with non-differentiating myeloid leukemia cells is prolonged by the injection of an inducer of cell differentiation with a sensitizer.

The effect of injection of an inducer and sensitizer on the survival times of syngeneic SL mice inoculated with resistant mouse myeloid leukemia cells (Ml) was examined. In vitro, the resistant Ml cells could not be induced to differentiate into mature macrophages and granulocytes by inducer (certain proteins, bacterial lipopolysaccharides, or glucocorticoids) alone, but could be induced to differentiate by treatment with both the inducer and a sensitizer (actinomycin D). In vivo, lipopolysaccharide alone scarcely affected the survival of SL mice inoculated with the resistant cells, but lipopolysaccharide plus actinomycin D significantly prolonged their survival. Administration of both lipopolysaccharide and actinomycin D also prolonged the survival of athymic nude mice inoculated with resistant Ml cells. These results suggest that prolongation of the survival of SL mice inoculated with resistant Ml cells is associated with the induction of differentiation of the cells.

Animals↗
PubMed1976

Erythroid cell differentiation: murine erythroleukemia cell variant with unique pattern of induction by polar compounds.

The murine-virus-infected erythroleukemia cell system provides an opportunity to examine regulatory mechanisms controlling cytodifferentiation. A cloned cell line (DR10c3) resistant to the erythropoiesis-inducing effect of dimethylsulfoxide (Me2SO) was isolated from the Me2SO-sensitive line DS19. DR10c3 is characterized as follows: (1) the uptake of [3H]Me2SO is similar to that in DS19; (2) cell growth with and without Me2SO is similar to that of DS19; (3) resistance is relatively stable; (4) the karyotype of DR10c3 reveals an average loss of five chromosomes per cell, but is otherwise similar to that of DS19; (5) total protein and globin synthesis by cells cultured 4 days with or without Me2SO is similar to these syntheses in DS19 cultured without Me2SO; (6) virtually no globin mRNA is detectable after 3 days in Me2SO, as assayed both by RNA-complementary DNA hybridization and by the heterologous cell-free protein-synthesizing system; (7) other polar compounds, N-methylpyrrolidinone, 1-methyl-2-piperidone, N, N-dimethylacetamide, and N-methylacetamide, induce erythroid differentiation in DR10c3, and the accumulation of alpha- and beta-globin chains is indistinguishable from that in DS19; and (8) the concentration optima for induction of differentiation by all these compounds are identical for DR10c3 and DS19.

Acetamides↗